Investigation of Partial Electrical Nerve Block for Autonomic Regulation

用于自主调节的部分电神经阻滞的研究 在美国，每年有超过60万人死于心脏病。心脏性猝死 常见于冠心病和/或患者的室性快速性心律失常(VT) 心衰(HF)。心脏病理后的自主神经失调是心力衰竭发生的关键 和VT。随着时间的推移，现有的干预措施缺乏反应时间、可逆性和适应性。因此，一个 尚未满足的主要需求是使用有针对性的、快速的、 可逆的、可分级的模式，对自主神经安全，最终可以长期部署。 在过去的十年里，电神经阻滞领域的进步已经显示出这一愿望的前景 治疗方式。周围神经传导阻滞起效快、可逆性好、分级好。先前 神经阻滞剂已经被用来完全阻断神经。这是第一次探索部分 堵住一根神经。部分电神经阻滞可以减轻自主神经反射，而不会使其熄灭。 然而，在任何期望的水平上，块的稳定性和可控性目前尚不清楚。理解 局部阻塞的特性将对自主系统的控制产生深远的影响。 心功能的闭环控制的可行性在很大程度上取决于实时的可用性 自主神经参数的反馈。现有的监测技术在响应性和 敏感度。为了提供实时控制源，将执行自主神经功能的直接记录 使用实时测量心脏间质和血管中儿茶酚胺。这一点的中心假设是 建议可以下调自主神经系统，维持对心脏的交感神经冲动 在临床相关的较低设定值使用DC阻滞剂。保持自主系统处于不同状态的能力 基于变化的心功能和心脏应激指数(例如室速负荷、心率)的特定设定点 将允许高度针对患者的疾病干预。具体地说，对于这项提案，目标是规范 功能交感神经控制心脏，并保持给定的设定值30分钟。目标1：确定和 描述在给定的设定点维持神经阻滞所需的部分神经阻滞的参数 迷走神经(自主神经)急性啮齿动物模型。目标2：确定心脏中的神经阻滞靶点 交感神经通路及部分阻断对诱发交感神经反射反应的影响 尤其是对封闭效果和恢复的影响。目的3：评价局部阻滞对心脏局部的影响 去甲肾上腺素释放快速扫描循环伏安法与高密度评价 局部心脏电功能。目的4：使用神经递质生物传感器，开发一种控制范式 确定何时启动阻塞以及确定阻塞级别。

Investigation of Partial Electrical Nerve Block for Autonomic Regulation More than 600,000 people die of heart disease in the United States every year. Sudden cardiac death often occurs as a result of ventricular tachyarrhythmias (VT) in patients with coronary heart disease (CHD) and/or heart failure (HF). Autonomic dysregulation following cardiac pathology is essential to the development of HF and VT. Existing interventions are lacking in response time, reversibility, and adaptability over time. Thus, a major unmet need is to impact/regulate sympathetic neural control of cardiac function using a targeted, rapid, reversible, and gradable modality that is safe for autonomic nerves and, ultimately, can be deployed chronically. Over the last decade, advances in the field of electrical nerve block, has shown promise to be this desired therapeutic modality. Peripheral electrical nerve block has a rapid onset, is reversible and gradable. Previously nerve block has been used to completely block a nerve. This is the first study to explore the value of partially blocking a nerve. Partial electrical nerve block can mitigate autonomic reflexes without extinguishing them. However, the stability and controllability of the block at any desired level are currently unknown. Understanding the characteristics of partial block would result in far reaching contributions to the control of autonomic systems. The feasibility of closed loop control of cardiac function is highly dependent on the availability of real time feedback of autonomic parameters. Existing monitoring techniques are lacking in both responsiveness and sensitivity. To provide a real-time control source, direct recording of autonomic nerve function will be performed using real-time measurements of cardiac interstitial and vascular catecholamines. The central hypothesis of this proposal is that the autonomic system can be down regulated and the sympathetic drive to the heart maintained at a clinically relevant lower set point using DC block. The ability to maintain the autonomic system at varying specified set points based on changing cardiac function and indices of cardiac stress (e.g VT burden, heart rate) would allow for highly patient specific disease interventions. Specifically, for this proposal, the goal is to regulate functional sympathetic control of the heart and maintain a given set point for 30 minutes. Aim 1: Identify and characterize the parameters of partial nerve block needed to maintain nerve block at a given set point using an acute rodent model on the vagus (autonomic) nerve. Aim 2: Identify nerve block targets in the cardiac sympathetic pathway and characterize the effect of partial block on evoked sympathetic reflex responses, in particular the effect on block efficacy and recovery. Aim 3: Evaluate the effect of partial block on regional cardiac norepinephrine using release fast scanning cyclic voltammetry in coordination with high density assessments of regional cardiac electrical function. Aim 4: Using the neurotransmitter biosensor, develop a control paradigm to determine both when to initiate block as well as determining the block level.